Neurobehavioral and genotoxic parameters of antipsychotic agent aripiprazole in mice

Abstract

Aim: Aripiprazole is an antipsychotic agent to treat schizophrenia, which acts through dopamine D 2 partial agonism, serotonin 5-HT 1A partial agonism and 5-HT 2A antagonism. This study was designed to evaluate the neurobehavioral effects and genotoxic/mutagenic activities of the agent, as well as its effects on lipoperoxidation. Methods: Open field and inhibitory avoidance tasks were used. Thirty min before performing the behavioral tasks, adult male CF-1 mice were administered aripiprazole (1, 3 or 10 mg/kg, ip) once for the acute treatment, or the same doses for 5 d for the subchronic treatment. Genotoxic effects were assessed using comet assay in the blood and brain tissues. Mutagenic effects were evaluated using bone marrow micronucleus test. Lipoperoxidation was assessed with thiobarbituric acid reactive substances (TBARS). Results: Acute and subchronic treatments significantly decreased the number of crossing and rearing in the open field task. Acute treatment significantly increased the step-down latency for both the short-and long-term memory in the inhibitory avoidance task. Subchronic treatments with aripiprazole (3 and 10 mg/kg) caused significant DNA strain-break damage in peripheral blood but not in the brain. Mutagenic effect was not detected in the acute and subchronic treatments. Nor TBARS levels in the liver were affected. Conclusion: Aripiprazole improved memory, but could impair motor activities in mice. The drug increased DNA damage in blood, but did not show mutagenic effects, suggesting that it might affect long-term genomic stability.Keywords: antipsychotic agent; aripiprazole; locomotion; memory; genotoxic/mutagenic activities; DNA damage; lipoperoxidation Acta Pharmacologica Sinica (2011Sinica ( ) 32: 1225Sinica ( -1232 doi: 10.1038/aps.2011 published online 15 Aug 2011 Original Article * To whom correspondence should be addressed. [8] .In the experimental context, Nagai et al [9] showed that aripiprazole that was administered as either a single dose or as consecutive doses (for 7 d) ameliorated phencyclidine-induced impairment of recognition memory in mice. However, another study showed that aripiprazole impaired the passiveavoidance response at doses near its anti-dopamine ED 50 (7.7 mg/kg, as defined by apomorphine stereotypy). At doses lower than those that affected the passive-avoidance response, aripiprazole was unable to reverse the MK-801-induced impairment in the same task [4] . Therefore, further investigations are necessary to elucidate the effect of aripiprazole on memory.The aim of the present study was to investigate the effects of aripiprazole on memory and on locomotor and exploratory activities with the inhibitory avoidance and open field tasks as behavioral models. Some drugs that affect memory can induce damage in biomolecules, such as lipids and DNA. Therefore, possible cytotoxic and genotoxic effects were evaluated by measuring lipid peroxidation in the liver and DNA strand breaks in both the peripheral blood and brain tissues after behavioral tasks. Mutagenic e...

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